Vaginal infections are a common problem among women. Bacterial Vaginosis (BV) is the most common form of infectious vaginitis, accounting for 45% of symptomatic cases and estimated to be present in 15% of asymptomatic sexually active women. See Breen, J. ed., The Gynecologist and the Older Patient, pp. 304-305 (1988). It is a polymicrobial vaginal infection believed to be caused by an increase in the number of anaerobic organisms with a concomitant decrease in lactobacilli in the vagina. The decrease in the number of lactobacilli in the vagina has a dual effect, i.e., (i) a decreased competition for nutrients, and (ii) a decrease in the amount of lactic acid present, thus allowing for the multiplication of opportunistic pathogens in the vagina, whose growth is normally suppressed by the lactobacilli. The principal pathogens associated with BV are believed to be Gardnerella vaginalis and anaerobes of the Mobiluncus species. However, numerous other pathogenic anaerobes are also believed to be involved in the etiology of vaginosis. See Kaufman et al., Benign Diseases of the Vulva and Vagina, 3rd ed., pp. 401-418 (1989). Thus, BV is considered a broad spectrum infection requiring a broad spectrum treatment.
In the United States discharge and foul smelling odor resulting from BV results in millions of women going to a physician's office each year in search of relief. An even larger number, estimated to be 30% of all adult American women, use douches that they purchase without a prescription. The idea of washing out the foul smelling discharge with an acid douche has a simplistic appeal. Medically, douching is frowned upon as studies have reported an association between douching and PID (Pelvic Inflammatory Disease), ectopic pregnancy, tubal infertility or reduced fertility. Furthermore, douching is unfavorable due to the fact that it also washes out normal and beneficial bacterial flora, leaving an environment prone to reoccurring BV.
The most troublesome aspect of BV is its impact upon the quality of fetal implantation and its potential to induce premature labor. The prevalence of BV in pregnant women has been reported to be 13 to 31%. BV during pregnancy is associated with increased risk of late miscarriage, pre-term labor, postpartum endometritis and low birth weight infants. In a recent study it was shown that BV is associated with an increased risk of miscarriage in the first trimester in women undergoing in-vitro fertilization.
U.S. application Ser. No. 09/748,753 discloses compositions useful in preventing miscarriage and premature labor associated with bacterial vaginosis by buffering the vaginal pH. The composition disclosed in the application comprises a therapeutically-effective amount of an aqueous pH-buffering bioadhesive water-insoluble, but water-swellable cross-linked polycarboxylic acid polymer, which provides the therapeutic effect without needing any additional treating agent, by itself buffering the vaginal pH to a normal, acidic pH, hostile to the infectant.
Clinically, BV presents itself as a superficial vaginal infection with few irritative symptoms and no inflammatory response. Some noticeable symptoms include an unpleasant smell, an elevated vaginal pH greater than about 5.0, a thin homogeneous discharge, the presence of Gardnerella clue cells and a high succinate/lactate ratio (not less than 0.4). See, e.g., Livengood et al., “Bacterial Vaginosis: Diagnostic and Pathogenic findings during Topical Clindamycin Therapy,” Am. J. Obstet. Gynecol., Vol. 163, No. 2, p. 515 (August 1990).
It is believed that the composition of organic acids in the vagina shifts from primarily lactic acid (pKa=3.86) to succinic acid (pKa1=4.27, pKa2=5.64) as a result of the decrease in lactobacilli, which produce lactic acid, and a rise in Mobiluncus, which produce succinic acid. This shift in acid composition tends to raise the vaginal pH. It is unclear whether the change in acidity is a cause or effect of the infection. However, it is known that certain undesirable anaerobes grow better at a higher pH than is normally present in the vagina. It is thus believed that lowering the vaginal pH to a normal healthy level is an effective measure against symptoms of the infection, if not the infection itself.
Moreover, the odor of the amines which are produced in the vagina during BV is known to increase at higher pH's because unprotonated, volatile amines are more prevalent at higher pH—as the environment becomes more basic. Additionally, the higher pH level is thought to allow the undesirable anaerobes to grow and produce the odor-causing amines that are associated with a bacterial vaginosis infection.
U.S. Pat. No. 6,017,521 (the “521 patent”) discloses a method of treating BV by topically contacting the luminal surface of vaginal epithelial cells with an effective pH buffering amount of an aqueous composition comprising water and an effective amount of a water-swellable, but water-insoluble, cross-linked pH buffering bioadhesive polymer wherein at least 80% of the monomers comprising said polymer contain at least one carboxyl group. The composition is kept in contact with the vaginal cells for a time period sufficient to lower the pH of the vagina to an acidic pH. The composition taught by the '521 patent is free of any treating agents.
The exact role of H2O2-producing lactobacilli is at best unclear. This may be the result of several factors the most important of which is concentration. Being able to detect H2O2-producing lactobacilli does not mean they are present in sufficient concentration to oxygenize the vagina and make the environment hostile to anaerobes. The solution many investigators have proposed is to add H2O2-producing lactobacilli to the vagina in high concentration as a means of eliminating the infection. The technical difficulties involved in such a project have prevented any investigator from developing a truly viable therapy.
Other attempts have been made to put H2O2 into a vaginal acidifier. However, those attempts have failed for two reasons. First, H2O2 is unstable in a gel and cannot be stored commercially. Second, the H2O2 concentration, which tends to be released quickly all at once, causing a “burst effect,” not only obliterates the anaerobes, but also sterilizes the vagina making women more susceptible to reoccurring vaginal infections.
Such a treatment is disclosed in U.S. Pat. No. 5,741,525, (the '“525 patent”). The '525 patent discloses methods for maintaining or enhancing the normal protective function of vaginal flora by administering a therapeutically effective amount of a composition that has hydrogen peroxide in an amount of about 0.1% to about 3.0%. The '525 patent teaches that peroxide “amounts below about 0.1% have been found to be unsuitable to have any meaningful inhibitory effect on a wide variety of microorganisms.” (The '525 patent at column 5, lines 57-59). The concentrations of hydrogen peroxide taught by the '525 patent to be useful in treating BV, however, are often detrimental to the growth of beneficial bacterial and can cause severe vaginal irritation and even vaginal peroxide bums. Furthermore, the treatment simply supplies a sudden burst of peroxide, killing a substantial number of bacteria and leaving it to chance as to whether a beneficial bacterial flora will recolonize or there will be a reoccurrence of BV.
Thus, there exists a need for an effective pharmaceutical composition for treating vaginal infections such as BV that does not have a “burst effect” causing vaginal irritation and excessively inhibiting or destroying beneficial bacterial flora. Furthermore, there is a need for a pharmaceutical composition that treats BV without sterilizing or significantly killing the normally-desired local vaginal flora the vagina and leaving it susceptible to reoccurring BV. There is also a need for a pharmaceutical composition that is simple to use and still effectively achieves a balance between inhibiting undesirable microorganisms, while providing a favorable environment for desirable local flora. The present invention successfully addresses these needs as detailed below.